运动锻炼刺激肾脏分泌ELABELA促进心梗小鼠心肌血管新生抑制心肌纤维化及其机制研究

The morbidity and mortality of cardiovascular diseases are increasing year by year. The proportion of myocardial infarction (MI) is very high, and it has become an important subject in clinical and rehabilitation medicine. Exercise promoting the recovery of cardiovascular diseases and the effect of distant organs on cardiac function has attracted much attention. The content of heart-derived ELABELA (ELA) is extremely low. The kidney is the main organ that secretes ELA which could be released into circulation. Myocardium also has the receptor of ELA. ELA has been found to have the cardiovascular protective effect. However, whether exercise can stimulate the secretion of ELA in the kidney to exert the protective effect in the distant organ——MI heart is still a blank. This project aims to explore the effect and mechanisms of exercise-stimulated renal ELA in promoting cardiac angiogenesis and inhibiting myocardial fibrosis in MI mice. In the present research, Both in vivo animal experiments and the recombinant protein injection will be conducted to investigate the role of ELA in aerobic exercise- and resistance exercise-stimulated myocardial angiogenesis induction and fibrosis inhibition; GFP labeled adeno-associated virus vectors will be used to confirm whether exercise-stimulated renal ELA could reach the MI heart through blood circulation and play a protective role; The molecular mechanisms of ELA in exercise-improved angiogenesis and inhibited myocardial fibrosis will be explored by in vitro cell experiments. This study may provide experimental basis for the filtration of rehabilitation methods and targets of ischemic heart.

心血管疾病患病率和死亡率逐年上升，其中心肌梗死占比甚高，是临床医学和康复医学的重大课题。运动促进心血管疾病康复、远隔器官对心功能的影响备受关注。心源性ELABELA（ELA）含量极低，肾脏是分泌ELA的主要器官并可释放进入循环，心肌存在ELA受体。研究发现ELA具有心血管保护作用，但运动是否可刺激肾脏ELA分泌产生远隔器官—心梗心脏保护效应，目前研究尚属空白。本项目旨在探索运动刺激肾源性ELA对心梗心肌血管新生和心肌纤维化抑制的作用及其机制。拟采用在体动物实验，通过重组蛋白构建体内注射，发现ELA在有氧运动和抗阻运动刺激心梗心肌血管新生及心肌纤维化抑制中的作用；拟通过GFP标记的腺相关病毒载体导入，确定运动刺激肾脏ELA是否经循环至心脏发挥保护作用；拟通过体外细胞实验，探究ELA在运动促进心梗心肌血管新生及心肌纤维化抑制中的分子机制。本研究将为缺血心脏康复手段及其靶点筛选提供实验依据。

“运动是良医”已成为国际运动科学领域的专家共识。开展重点人群的运动干预，特别是心血管疾病的运动康复以及心血管功能与运动调控，均是亟待深入研究的健康科学问题。在本项目的资助下，我们开展了外源性ELABELA（ELA）和肾源性ELA对运动保护缺血心脏的作用和机制研究。结果发现，有氧运动在保护心梗心脏的同时，上调大鼠心脏、血清和肾脏局部ELA表征。外源性ELA蛋白注射可以促进心梗心脏血管新生、抑制心肌病理性重塑，改善心功能，且ELA-APJ-Akt / YAP信号轴是有氧运动保护心梗心脏的重要机制。本项目研究首次证实有氧运动刺激肾源性ELA内分泌，经血液循环至心梗心脏发挥保护作用，并通过TGFβ-Smad2/3信号通路改善心梗小鼠心肌纤维化。在围绕远隔器官保护缺血心脏方面，我们也首次发现并证实动态抗阻运动增强骨骼肌源性FSTL1，通过DIP2A-Smad2/3诱导心梗心脏血管生成。此外，有氧运动通过激活FGF21/FGFR1/PI3K/AKT通路或抑制ALCAT1的高表达，减轻氧化应激和细胞凋亡；抗阻运动通过激活Irisin/FNDC5-PINK1/Parkin-LC3/P62通路，调节线粒体自噬，抑制氧化应激，最终改善心梗小鼠的心功能。共发表SCI论文3篇、出版学术专著1部，发表会议论文3篇，培养硕士研究生3人，获得陕西高等学校科学技术研究优秀成果二等奖，多次参加国内外学术会议并进行专题报告。基于本项目成果，美国马里兰大学医学院已开始关于ELABELA临床药物的开发工作；出版的学术专著作为科普类书籍，为普通人群健康水平的提高和临床患者运动康复的方案提供了理论依据。